The past (a brief history of epinephrine use in cardiac arrest)

In 1901 Jokichi Takamine (1854-1922) isolated the pure form of adrenaline, also known as epinephrine.

Routine use of adrenaline for cardiac arrest was first proposed in the 1960’s. Its inclusion within cardiac arrest management was based upon an understanding of the physiological role of adrenaline, and experimental data from animal research which showed that ROSC was more likely when the drug was used.

Epinephrine was not included in cardiac arrest protocols on the basis of evidence of benefit in humans.

Higher is the coronary pressure perfusion (CPP), greater is the chance of ROSC.

Epinephrine is a key determinant factor in maintaining diastolic aortic pressure in cardiac arrest; thanks to its interaction with alpha receptors, located on the endothelium of the arteries, produce generalized peripheral arterial vasoconstriction maintaining aortic diastolic pressure to a high level even during chest compressions.

The cut off value for ROSC is 15 mmHg of CPP, but more is better (at least 40 mmHg9.

Many and strong recent evidences demonstrates that “Among patients with OHCA, use of prehospital epinephrine was significantly associated with increased chance of return of spontaneous circulation before hospital arrival but decreased chance of survival and good functional outcomes

The Present: PARAMEDIC 2 trial.

What kind of study is this:

Randomized, double-blind, multicentric.

Population

8014 patients with out-of-hospital cardiac arrest in the United Kingdom

Inclusion Criteria

Adult (>16 years) patients, transported by five National Health Service ambulance services in the United Kingdom, who had sustained an out-of-hospital cardiac arrest for which advanced life support was provided by trial-trained paramedics.

Exclusion criteria

Apparent pregnancy, age of less than 16 years, cardiac arrest from anaphylaxis or asthma, administration of epinephrine before the arrival of the trial-trained paramedic.

Conclusions

In adults with out-of-hospital cardiac arrest, the use of epinephrine resulted in a significantly higher rate of 30-day survival than the use of placebo, but there was no significant between-group difference in the rate of a favorable neurologic outcome because more survivors had severe neurologic impairment in the epinephrine group.

Strengths

Randomized, multicenter, double blind, placebo controlled

8014 patients randomised.

Well balanced characteristics at baseline of the two groups

Concurrent treatments were similar

Median time from the emergency call to ambulance arrival was 6.6 minutes

Patient oriented outcomes

Limitations

Overall survival rate in this trial was disappointingly small (3.2% and 2.4%, respectively)

615 patients where excluded because had return of spontaneous circulation before paramedics can open the trial pack. Of these 615 patients of which we don’t know the clinical outcome but including the survivors overall survival rate is similar to other EMS in Europe.

Median time from the emergency call until administration of the trial agent 21 min and we know (according the other studies) that cardiac arrest has 3 phases (Electrical Phase, first 5 min (Defib), Circulatory Phase next 10 – 15min (Chest compressions), Metabolic Phase 10-20min) and epinephrin is effective if administered in the first 20 min of the cardiac arrest.

Information about the quality of CPR was limitedto the first 5 minutes of cardiac arrest and involved <5% of enrolled patients

The protocol neither controlled nor measured in-hospital treatments and we know that the most common cause of in-hospital death is iatrogenic limitation of life support, which may result in the death of potentially viable patients.

What we know till today

Epinephrine in cardiac arrest improve ROSC and patients alive.

The improved survival is mostly due to patients with bad (<3 MRS) neurological outcome.

What that means

Administering the current recommended dose of Epinephrine we have to choose between numbers and quality of life.

Patients clearly said quality of life is more important

Epinephrine is anyway important because having bigger numbers of ROSC give the chance to improve neurological outcomes.

Future challenges

Understanding why epinephrine doesn’t work and can be detrimental on long term neurological outcome.

Obtaining more ROSC and better neurological outcomes in Cardiac Arrest

The (im)possible future

I think there are two key factors, in the actual way to use Epinephrine, that determine its failure:

The wrong administration route

When epinephrine is administered intravenously in a low flow state patient (as is a patient during cardiac arrest, even if proper chest compressions are performed), the amount of drug that arrives to perform the “local” alpha effect on arteries is just a minimal quantity of the (high!!!) dose. The major part rely in the venous circulation and is mobilized in great quantity only when ROSC happens determining a widespread vasoconstriction and a consequent “overdose” effect (think just at the “stunned” myocardium that has to overwhelm such ha great post-load work).

The wrong dose to the wrong patient

From the coronary perfusion pressure (CPP) point of view, every cardiac arrest patient is different: some patients have a (relative) good aortic pressure and a (relative) good coronary perfusione comparing to others.

When we administer the same amount of epinephrine to each of them this takes to an underdose in some patients (with low flow state) and an overdose in others (with good or high flow state).

So now what?

The right administration route

Probably the best route to administer epinephrine is not the vein but the artery.

It allows, even in a low flow state patient, a better chance to reach the vasoconstrictor effect maintaining a good aortic diastolic pressure and a consequent good coronary flow.

The right dose to the right patient

Giving epinephrine (standard dose) to a patient who has a low flow state (patients who need it more) make epinephrine usefulness (underdose) because just a little part of it circulate.

Giving epinephrine to patients in a good or high flow state (patients that need it less or don’t need epi at all) is detrimental and can cause overdose effect.

We need to know wich is the circulatory state of the patients to administer the right dose avoiding the “overdose” effect.

The only way to do this is monitoring aortic diastolic pressure through an arterial catheter. We can target Epinephrine dosage to reach a good aortic pressure maintaining a good CPP (achieving ROSC) and avoiding overdose.

Take home messages for future improvements in cardiac arrest management

A 2017 study about US and cardiac arrest aroused the debate about using POCUS during cardiac arrest . The authors concluded that:

“The use of POCUS during cardiac arrest resuscitation was associated with significantly increased duration of pulse checks, nearly doubling the 10-s maximum duration recommended in current guidelines.”

THE QUESTION

Is POCUS an unuseful loose of time and a potential KILLER when used on patients in Cardiac Arrest?

In my personal experience (and in the EMS where I work) we tried to give an answer to this question formulating a structured approach to use ultrasound during a code. The objective is to have vital information from the probe without delays or interruption in chest compressions.

THE RATIONALE

In WHICH cardiac arrest using POCUS really worths the price?

For sure PEA and Asistoly are the the most relevant conditions to use a probe, on the contrary in defibrillating rhythms, defibrillation and anti-arythmic therapy is a priority, and no useful information can come from ultrasound.

So look at the monitor, if there is a defibrillating rhythm continue with classical ALS approach.

Use a probe only if Asystoly or a PEA are present.

WHENwe use the probe?

The right moment is during the 10 seconds pause indicated from guidelines to asses the rhythm.

Look at the monitor screen for rhythm check and place the probe on the patient for no longer than 10 seconds.

WHEREwe place the probe.

SubCOSTAL view of the heart for heart beating

SubCOSTAL view of the heart pericardial effusion and VD>VS

Left CHEST view for lung sliding

Right CHEST view for lung slinging

WHAT we can identify with ultrasound during Cardiac Arrest.

First thing is there any cardiac activity?

We no more check the pulse, but rely on indirect signs of cardiac arrest when starting chest compressions, but at the beginning of the code and during the reanimation, cardiac activity is a game changing information.

Second thing is does exists any reversible cause of Cardiac Arrest?

Addressing and treating those can really change the outcome of the patient.

Pulmonary Embolism

Cardiac Tamponade

Tension Pneumo

Hypovolemia

The method

During the 10 sec pause asses the rhythm and place the probe .

During the following 2 min CPR think and address, when indicated, the reversible causes.

THE SCHEDULE

HEART BEATING

If heart is beating and the rhythm is Asystoly think to an equipment problem or to a very fine VF.

If the heart is beating and we have a PEA this is not a true PEA but a pseudo PEA so we have to treat this patient as a profound shock patient (POCUS differential diagnosis for shock) more than CA patient.

If heart is not beating, any rhythm, we look for reversible cause of CA.

PERICARDIAL EFFUSION

VD>VS

If pericardial effusion is present think at CARDIAC TAMPONADE

If VD>VS think at PULMONARY EMBOLISM

If no one of that are present go to the following step

Lung Sliding

If lung sliding is absent think at a selective intubation of the right main bronchus or at a PNX. If lung sliding is present go to the following step.

Lung Sliding

If lung sliding is absent think at a PNX.

Can we scan more during 2 min CPR?

Left flank and look for free fluid.

Right flank and look for free fluid.

If there is free fluid in the abdomen think and treat HYPOVOLEMIA.

REMEMBER! At any time during the code, if EtCO2 rises or a coordinated electric activity is present

NO PULSE CHECK

USE ULTRASOUND TO IDENTIFY A BEATING HEART

TRUST THE PROBE NOT YOUR FINGERS

If no reversible cause are detected, and the patient is still in non defibrillating rhythm, check the heart and the EtCO2.

If heart is not beating and EtCO2 level is less than 10 mmHg. during good quality chest compressions, consider to call the code.